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Peptide absorption

Peptide absorption: where peptides fit in protein nutrition and metabolism

Published: May 16, 2007
By: JAMES C. MATTHEWS - Alltech Inc.

Research over the last 30 years has demonstrated that the absorption of amino acids in the form of oligopeptides (principally di- to tri-peptides) constitutes the most quantitatively important form of amino acid uptake from digesta by gut epithelia (Matthews and Adibi, 1976; Steinhardt and Adibi, 1986; Matthews, 1991; Seal and Parker 1991; Webb et al., 1992; Koeln et al., 1993; Gardner, 1994) and physiologically important amounts from glomerular filtrate by renal epithelia (Daniel et al., 1992; Adibi, 1997).

In contrast, quantitatively important amounts of intact oligopeptide absorption by liver and skeletal muscle is thought not to occur (Adibi, 1997), whereas the physiological significance and form of circulating peptides to support the function of other peripheral tissues is under investigation (Kee et al., 1994; Backwell, 1998; Webb and Matthews, 1998; Dieck et al., 1999; Power and Murphy, 1999). Given the significance of peptide absorption to wholeanimal protein nutrition, an understanding of the mechanisms by which peptides are absorbed, where they are expressed, and the potential to regulate these events, is of fundamental importance to nutritionists.


Peptide absorption mechanisms

The expression of proteins that are capable of recognizing and transporting peptide-bound amino acids across cellular membranes appears to be a universal phenomenon; Gram-negative and Gram-positive bacteria, fungi, the seeds of many cereal grains, round worms, fruit flies, and many types of animal cells have been shown to be capable of intact peptide absorption. From the pioneering work of David Matthews (Matthews, 1991), Siamak Adibi (Adibi, 1997), and Fredrick Leibach and Vadivel Ganapathy (Ganapathy et al., 1994; Leibach and Ganapathy, 1996) we now understand that digesta and plasma proteins do not need to be completely hydrolyzed to their constituent amino acids for absorption to occur by discrete transport proteins.

Owing to the work of these and many other researchers, three peptide transport activities have been biochemically characterized in mammals: 1) a low-affinity transport system that is highly expressed in the apical membranes of differentiated enterocytes, which also is weakly expressed in the microvillus membrane of kidney tubule epithelia, 2) a high-affinity transport capacity primarily expressed in the apical membranes of kidney proximal tubules epithelia, and 3) a low-affinity system on the basolateral membranes of polarized cell types that displays a more limited range of transport capacity than the low-affinity apical transporters.

From this understanding, a generalized model (Ganapathy et al., 1994) has emerged to account for how peptide-bound amino acids are absorbed across mammalian polarized epithelia: 1) peptides are recognized and translocated through the apical membrane into the cell cytosol by a H+-coupled, concentrative, low-affinity, high-capacity transporter, 2) hydrolysis of the peptide to free amino acids occurs, followed by transport into the blood by amino acid transporters, or 3) passage of intact peptides across the basolateral membrane into the blood is achieved by a high-affinity, low-capacity membrane transporter (Ganapathy et al., 1994; Adibi, 1997; Steel et al., 1997).

Currently under investigation is whether the basolateral transporter is H+- dependent (Thwaites et al., 1993) or a facilitative (Terada et al., 1999) transporter. The proportion of peptides that actually survive transepithelial passage from the lumen into the blood is typically estimated as 10 to 20% for enterocytes (Ganapathy et al., 1994) and virtually 0% for renal absorptive cells (Adibi, 1997). In ruminant forestomach tissue, a single report for one peptide (methionylglycine) suggests that omasal tissue has a greater ability to hydrolyze absorbed peptides (95%) than does ruminal epithelium (64%) (Matthews and Webb, 1995). In terms of energy expenditure, the H+/peptide cotransport is classified as a tertiary transporter (Ganapathy et al., 1994). That is, after H+ are cotransported with small peptides across the apical membranes of enterocytes and released into the cytoplasm by the H+/peptide cotransporter, H+ are then pumped out of the cell by the apical membrane-bound Na+/H+ exchanger (driven by the extracellular-tointracellular Na+ gradient), thereby reestablishing the extracellular-to-intracellular H+ gradient. The activity of the basalateral Na+/K+ ATPase then reestablishes the high extracellular-to-intracellular Na+ gradient with the expenditure of ATP.

The cloning of nucleic acid sequences that encode peptide transporters has clarified several apparent anomalies that existed between the low-affinity, high-capacity transport activity that predominates in the intestinal epithelia and the high-affinity/lower-capacity activity that predominates in renal tissue. PepT1 (Peptide Transporter 1; 707 amino acid polypeptide for rabbit and 708 amino acids for human) complementary (c) DNA encodes a lowaffinity, high-capacity transporter that is predicted to contain one relatively large cytosolic domain and twelve alpha-helical membrane-spanning domains (Fei et al., 1994). PepT2 (Liu et al., 1995) cDNA encodes for a high-affinity, low-capacity transporter that is predicted to consist of 729 amino acids and possess 12 membrane-spanning domains (Leibach and Ganapathy, 1996). The amino acid sequences for human PepT1 and PepT2 share 50% identity, with the majority of the homology existing in the membrane- spanning regions.

When the putative basolateral peptide transporter (Thwaites et al., 1993) is cloned, of particular interest will be whether the transporter functions to couple H+ to pump peptides out of the cell or as a facilitative transporter, whereby substrate concentration gradients will drive transport. In accordance with the biochemically defined H+/peptide cotransport activity, functional expression of PepT1 or PepT2 in various experimental models has shown that maximal peptide uptake occurs in the presence of an extracellular pH of 5.5 to 6.0. However, significant (25 to 50%) peptide uptake does occur from pH 6.0 to 7.0. With regard to the stoichiometry of H+/peptide cotransport, expression studies have shown that the number of H+ required for peptide transport across the apical membrane of enterocytes depends on the charge of the substrate. For example, PepT1 displays H+:substrate ratios of 1:1, 2:1, and 1:1 for neutral, acidic and basic dipeptides, respectively (Steel et al., 1997), whereas PepT2 displays H+:substrate ratios of 2:1 and 3:1 for neutral and basic substrates (Chen et al., 1999b). Whether acidic peptides are relatively less well recognized in the presence of a lower pH than are neutral or basic dipeptides, has not been definitively established, as evidenced by the contradictory data from whole tissue (Lister et al., 1997) versus in vitro (Brandsch et al., 1997) studies.

A salient, and potentially useful feature of peptide transporters to nutritionists and pharmacologists alike, is the ability of PepT1 and PepT2 to recognize a wide variety of substrates. This relatively high degree of transport ‘promiscuity’ is thought to result from the need to potentially recognize over four hundred dipeptides and 8000 tripeptides that result from the digestion of ‘typical’ proteins (Ganapathy et al., 1994). Consistent with the relatively few transport systems that have been identified for peptide transport, recognition by these ‘promiscuous’ transporters has been proposed to be achieved with an oligopeptide of four or less amino acids that contains at least one peptide bond, a carboxy- terminal ‘L’ conformer amino acid, and an overall net positive charge of less than two (Boyd, 1995). Accordingly, ß-lactam and cephalosporin antibiotics are substrates for peptide transport systems. Recently, however, even the requirement for a peptide bond has been questioned (Ganapathy et al., 1998). Despite these relatively flexible requirements for recognition, substantial differences exist in substrate binding affinities among peptide transporters (Brandsch et al., 1998; for a summary of Km values see Matthews, 2000).


Expression of peptide transporter activity and mRNA

As noted earlier, the seminal research by Matthews and Adibi has resulted in the acceptance that a substantial portion, and likely the majority, of amino acids are absorbed from intestinal digesta in the form of oligopeptides, rather than as free amino acids. Given what we know about the biochemical and molecular characterization of cloned peptide transporters, it is also accepted that the mechanism of peptide absorption primarily is by PepT1, with, perhaps, some contribution by PepT2. Consistent with this understanding, rabbit PepT1 mRNA expression is greatest by epithelial cells of the small intestine, especially the jejunum, less by the liver and kidney tissue, and least by several brain tissues (Fei et al., 1994). In rats, PepT1 mRNA expression by duodenal, jejunal, and ileal epithelia is reported to be equal (Erickson et al., 1995).

However, immunohistochemical analysis indicates that whereas PepT1 is expressed in all small intestinal epithelia, it is most abundant in the jejunum of rats (Ogihara et al., 1999). Similar to the localization of SGLT1 (Na+- dependent) and GLUT2 (Na+-independent) glucose transporters, PepT1 protein is most abundant in the villus tip, decreasing in concentration into the crypt, but absent from goblet cells and undifferentiated basal cells (Ogihara et al., 1999). This localization of greatest PepT1 mRNA content in the villus tip is consistent with the identification of the villus tip as being the site of greatest PepT1 activity in rabbits (Tomita et al., 1995).

In contrast to the pattern for PepT1 expression, rabbit PepT2 mRNA expression was greatest by the kidney, and weaker by brain, lung, liver, heart and spleen tissues (Boll et al., 1996). The dual expression of PepT1 and PepT2 in the kidney is consistent with the biochemically defined highand low-affinity peptide transport systems (Daniel et al., 1992). The concentration of peptides is thought to increase from the proximal to distal nephron as a result of the high apical membrane-bound peptidase activity of renal absorptive cells (Adibi, 1997). Accordingly, future immunohistochemical research is expected to reveal that PepT1 is expressed predominately in the distal region of nephrons while PepT2 will be primarily expressed in the proximal nephron region (Leibach and Ganapathy, 1996).

There is little biochemical evidence to indicate that muscle tissue possesses the capacity for H+/peptide cotransport (Ganapathy et al., 1994; Adibi, 1997). A recent negative examination (Chen et al., 1999a) of skeletal muscle for PepT1 mRNA expression in pig, chicken, sheep and cattle supports this concept. In the liver, the ability and degree to which peptides are absorbed is controversial. Despite the detection of PepT1 mRNA in rabbit liver, and the demonstration of mediated uptake of carnosine and glycylsarcosine in hamster liver slices (Matthews, 1991), the quantitative importance of hepatic peptide absorption is challenged by the observation that rat hepatocytes were incapable of absorbing dipeptides that are less resistant to hydrolysis than glycylsarcosine and carnosine (Lochs et al., 1986). Instead, it is proposed that the absorption of peptide-bound amino acids occurs only after hydrolysis to their constituent amino acids. These discrepancies could be the result of species-specific differences or, alternatively, the expression of transporter protein may be limited to membranes other than the plasma membrane. In support of this hypothesis, low-affinity peptide transport activity has been demonstrated in the lysosomal membranes of rat hepatocytes using glycylglutamine (Thamotharan et al., 1996).

Compared to humans and laboratory species, little is known about the specific biochemical activities and mechanisms responsible for the absorption of peptides by farm animal species. However, it has been known for a number of years that peptide absorption accounts for a substantial component of the total amino acid absorption by the gastrointestinal tract of chickens (Duke, 1984). H+/peptide cotransport activity has been measured in brush border membranes of the small intestine, ceca, and rectum of chicks (Calonge et al., 1990). Consistent with the identification of H+/peptide transport activity in the small intestine, but not with that of the ceca and colon, Northern blot analysis has identified the presence of PepT1 mRNA in duodenal (primarily), jejunal, and ileal epithelia, but not in other gastrointestinal tissue of White leghorns and broilers (Chen et al., 1999a). For pigs, in vivo research suggests that amino acids are more readily absorbed as oligopeptides than as free amino acids (Rerat et al., 1992). The dual expression of PepT1 mRNA and H+-dependent peptide uptake capacity by jejunal tissue of growing (27 to 100 kg) pigs (Winckler et al., 1999) suggests that the capacity for porcine small intestinal uptake of oligopeptides is through the functioning of PepT1.

As a corollary to arterial-venous flux studies that indicate nutritionally significant amounts of oligopeptides are absorbed across the gastrointestinal tract of sheep and cattle (Seal and Parker, 1991; Webb et al, 1992, Koeln et al., 1993; Webb and Matthews, 1998), ruminants should possess H+/peptide cotransport activities and proteins in mesenteric- and non-mesenteric- drained epithelia. With regard to the potential mechanism of intestinal absorption, preliminary reports indicated that epithelia of the ruminant small intestine express both PepT1- and PepT2-like functional activity. Using brush border membranes isolated from duodenal epithelium of sheep, a Km value of 0.005 mM for Gly-Pro was observed (Backwell et al., 1995), consistent with substrate affinity constants typically reported for high-affinity/ low-capacity transport by PepT2. Uptake velocities measured for peptide transport by proximal intestinal tissue of sheep and cattle (Dyer et al., 1996), however, are consistent with those reported for low-affinity, high capacity PepT1 transport activity. The findings that jejunal and ileal brush border membranes of cattle express glycylsarcosine affinity constants of 1.3 and .93 mM (Wolffram et al., 1998), and that cattle duodenal, jejunal, and ileal epithelial tissues express PepT1 mRNA (Chen et al., 1999a), provide strong corroborating evidence that bovine small intestinal epithelium possesses PepT1 transport activity.

The study of the capacity of forestomach tissues (rumen, reticulum, omasum) to absorb peptides is complicated by the structural arrangement of their keratinized, stratified squamous epithelia. However, given that 1) the typical acidity of the rumen liquor is sufficient to drive transport of peptides by PepT1 or PepT2, 2) Na+/H+ exchanger and Na+/K+ ATPase proteins essential for reestablishing H+ gradients in epithelial cells exist and function in both ruminal and omasal epithelia, and 3) that the forestomach liquor contains significant amounts of small peptides (for a summary see Matthews et al., 1996a), it is not surprising that recent research discovered that forestomach epithelia do possess the ability to absorb small peptides. That dipeptides were capable of intact passage across the complex forestomach epithelium initially was demonstrated by the transepithelial passage of intact carnosine and methionylglycine across sheep ruminal and omasal epithelial sheets mounted parabiotic chambers (Matthews and Webb, 1995). That absorption probably was the result of mediated transport is indicated by detection of mRNA capable of encoding PepT1-like activity using functional expression studies with Xenopus laevis oocyte studies (Matthews et al., 1996b; Pan et al., 1997). Subsequently, a partial-length cDNA that shared nucleic acid sequence homology to rabbit, rat, and human PepT1 cDNAs was cloned from omasal mRNA and used to detect the expression of PepT1 mRNA in both rumen and omasal epithelia (Chen et al., 1999a).


Regulation of H+/peptide cotransport capacity

Given the importance of H+/peptide transport activity to total amino acid absorption, it is of immense interest to understand whether PepT1 transport capacity can be regulated. However, research investigating the ability of dietary substrates to alter peptide absorption capacity is limited. In mice fed a high-protein (72%) versus low-protein (18%) diet, peptide uptake capacity was increased 30 to 70% in duodenal and jejunal, but not ileal, tissue (Ferraris et al., 1988).

However, when equal amounts of a 54% non-hydrolyzed, partially-hydrolyzed, or completely hydrolyzed casein diet were fed, no difference in peptide uptake capacity was observed. The ability of dietary protein content to directly modulate PepT1 expression has been investigated by comparing the amount of PepT1 mRNA expressed in small intestinal epithelia collected from rats fed a diet that contained 17.5% casein (control diet) for seven days to that by rats fed an isocaloric diet that contained 50% gelatin (high protein diet) for 14 days (Erickson et al., 1995). The amount of PepT1 mRNA was increased about 2-fold in the mid and proximal small intestinal epithelia of rats fed the high-protein diet. Subsequently, the potential for substrate stimulation of PepT1 that was independent of hormonal influences, and by a single substrate, was evaluated using Caco-2 cells (Walker et al., 1998). The culture of cells in glutaminylglutamate media for three days resulted in a 1.6-fold increase in Hs+-dependent peptide transport that was accompanied by a 2-fold increase in both PepT1 mRNA and protein. Overall, the study demonstrated that the increase in peptide transport capacity was the result of an increased rate of mRNA transcription and mRNA stability. Although limited, these data, generated from a variety of experimental models, suggest that peptide transport capacity is sensitive to substrate regulation.

Besides evaluating the effects of increased substrate supply on peptide transport capacity, the effect of dietary substrate deprivation (fasting) on PepT1 expression has been investigated. In rats fasted for one day, peptide uptake capacity increased 2-fold, concomitant with a 3-fold increase in PepT1 mRNA in intestinal mucosa and PepT1 protein in its apical membranes (Thamotharan et al., 1999b). Accordingly, fasting appeared to stimulate a general increase in PepT1 gene expression. These results are consistent with another study that found that the influence of a longer (4-day) fast was to increase the amount of PepT1 protein present in the villus tips of jejunal tissue of fasted rats, as compared to rats fed normal amounts of rat chow (Ogihara et al., 1999). In contrast, however, when fasted rats were given a liquid free amino acid supplement, the jejunal expression of PepT1 protein was reduced. This observed ability of the presence of free amino acids to down-regulate peptide transport capacity merits further investigation to determine whether this is a general response, or one that is restricted to the employed experimental regimen.

The potential regulation of peptide transport capacity by hormones has been studied using Caco-2 cells. Physiological levels of insulin stimulated the ‘recruitment’ of previously synthesized PepT1 proteins from cytoplasmic stores, in a manner apparently analogous to the insulin-dependent stimulation of facilitated glucose transport activity (Thamotharan et al., 1999a).

Accordingly, insulin-dependent stimulation of PepT1 activity appears to be a transcription- and de novo protein synthesis-independent, but microtubule- dependent process. If in vivo studies confirm these results, then it is very likely that PepT1 activity in intestinal epithelia can be rapidly modulated in response to substrate availability. In contrast, upregulation of PepT1 activity in Caco-2 cells through stimulation of σ1 receptors (Fujita et al., 1999) is concomitant with an increase in PepT1 mRNA. Although not fully characterized, progesterone is thought to be a ligand for F1 receptors. Accordingly, it is speculated that toward late gestation, when nutrient demands are elevated for prolonged periods, that increased progesterone levels act to stimulate the capacity for amino acid absorption by increasing peptide transport capacity.


Conclusions

The absorption of amino acids as oligopeptides constitutes the greatest form of amino acid absorption by gastrointestinal tissues. PepT1 is the primary transporter responsible for this H+-coupled activity and is predominately expressed in the villus tips of small intestinal tissue of mammals. In addition, the evidence is strong for PepT1 expression in forestomach epithelia of ruminants. PepT2 is the principle peptide transporter expressed in the proximal tubules, where it functions to resorb peptides from the glomerular filtrate. There is little evidence to suggest that liver or skeletal muscle absorbs intact peptides. Though limited, initial studies indicate that expression of PepT1- mediated peptide absorption capacity is highly sensitive to substrate surfeit, substrate deficit, and hormonal factors. Unresolved questions regarding peptide absorption include: 1) what is the capacity for peptide-bound versus free amino acid uptake by the gastrointestinal epithelia, 2) can this capacity be regulated in vivo by diet and (or) feeding regimens, and, if so, 3) will increasing the amount of peptide-bound amino acids achieve greater amino acid absorption efficiencies, and 4) is the development and use of ‘model’ peptides and (or) protein hydrolysates to potentiate peptide absorption capacity economically feasible.



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Author: JAMES C. MATTHEWS
University of Kentucky, Lexington, Kentucky, USA
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